Article

Role of myeloid cells in vascular endothelial growth factor-independent tumor angiogenesis

Genentech, Inc., 1 DNA Way, South San Francisco, California, USA.
Current opinion in hematology (Impact Factor: 4.05). 03/2010; 17(3):219-24. DOI: 10.1097/MOH.0b013e3283386660
Source: PubMed

ABSTRACT Targeting the vascular endothelial growth factor (VEGF) pathway has had a significant impact in the therapy of cancer and intraocular neovascular disorders. Similar to other therapies, inherent/acquired resistance to anti-VEGF drugs may occur in cancer patients, leading to disease recurrence. This review describes recent findings on the role of myeloid cells in refractoriness or/and acquired resistance to such therapies.
Various myeloid cell types, including tumor-associated macrophages, Tie2-expressing monocytes and neutrophils, have been implicated in tumor angiogenesis. Several cytokines involved in the mobilization and/or proangiogenic effects of these cells represent therapeutic targets. CD11b+Gr1+ myeloid cells have been shown to render tumors refractory to angiogenic blockade by VEGF antibodies. This effect was mediated by the secreted protein Bv8, which is upregulated by granulocyte colony-stimulating factor.
Progress in unraveling proangiogenic mechanisms dependent on various myeloid cell types has expanded our understanding of tumor angiogenesis and has generated a number of potential therapeutic targets.

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    • "These cells communicate by means of a complex network of intercellular signaling pathways mediated by surface adhesion molecules, cytokines and their receptors. These infiltrating immune cells, generate an environment abundant in growth and angiogenic factors and are implicated in enhancing cancer growth and subsequent resistance to therapy [4] [75]. The inflammatory cytokines interleukin (IL)-1alpha and IL-1beta as well as a wide panel of other signaling molecules produced by infiltrated inflammatory cells including VEGF and matrix-metalloproteinases (MMPs) may contribute to angiogenesis, tumor proliferation, and local invasion of cancer [76] [77]. "
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    ABSTRACT: Deregulation of angiogenesis–the growth of new blood vessels from an existing vasculature–is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding “the most important target” may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the “Halifax Project” within the “Getting to know cancer” framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy; 1) endothelial cell migration/tip cell formation, 2) structural abnormalities of tumor vessels, 3) hypoxia, 4) lymphangiogenesis, 5) elevated interstitial fluid pressure, 6) poor perfusion, 7) disrupted circadian rhythms, 8) tumor promoting inflammation, 9) tumor promoting fibroblasts and 10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds; 1) oleic acid, 2) tripterine, 3) silibinin, 4) curcumin, 5) epigallocatechin-gallate, 6) kaempferol, 7) melatonin, 8) enterolactone, 9) withaferin A and 10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the “hallmarks” of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.
    Seminars in Cancer Biology 01/2015; · 9.33 Impact Factor
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    • "These cells communicate by means of a complex network of intercellular signaling pathways mediated by surface adhesion molecules, cytokines and their receptors. These infiltrating immune cells, generate an environment abundant in growth and angiogenic factors and are implicated in enhancing cancer growth and subsequent resistance to therapy [4] [75]. The inflammatory cytokines interleukin (IL)-1alpha and IL-1beta as well as a wide panel of other signaling molecules produced by infiltrated inflammatory cells including VEGF and matrix-metalloproteinases (MMPs) may contribute to angiogenesis, tumor proliferation, and local invasion of cancer [76] [77]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Deregulation of angiogenesis – the growth of new blood vessels from an existing vasculature – is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding “the most important target” may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the “Halifax Project” within the “Getting to know cancer” framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the “hallmarks” of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.
    Seminars in Cancer Biology 01/2015; (ePub ahead of print). DOI:10.1016/j.semcancer.2015.01.001 · 9.33 Impact Factor
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    • "Accordingly, tumour cells lacking AMPK activity are expected to undergo necrosis following anti-angiogenic therapy, due to their incapacity to maintain ATP levels. Although in patients the association between tumour necrosis and outcome of antiangiogenic therapy is not firmly established, in preclinical models necrosis often leads to increased recruitment into tumours of macrophages and other specialised subsets of myeloid cells which can promote tumour angiogenesis and leads to escape from VEGF blockade (Ferrara, 2010). Therefore, defective AMPK activity might be predicted to associate initially with improved tumour response, followed by increased resistance to VEGF neutralisation. "
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    ABSTRACT: Background: AMP-activated protein kinase (AMPK) has a central role in cellular energy sensing and is activated in preclinical tumour models following anti-vascular endothelial growth factor (VEGF) therapy. The possible predictive or prognostic role of AMPK status in cancer patients treated with anti-VEGF drugs has not been investigated so far. Methods: Expression of components of the AMPK pathway including phosphorylated AMPK (pAMPK), phosphorylated acetyl-Coa carboxylase (pACC) and liver kinase B1 (LKB1) was investigated by immunohistochemistry in 48 colorectal cancers treated with FOLFIRI plus bevacizumab. Correlation between pAMPK and pACC and associations between the AMPK pathway scores and clinico-pathological characteristics were assessed. Overall survival (OS) was estimated through Kaplan–Meier method, whereas hazard ratios were computed to identify prognostic factors. Results: Fourteen patients (29.2%) were included in the pAMPK-negative group (score ⩽5), whereas 34 patients (70.8%) were included in the pAMPK-positive group (score >5). The Spearman's coefficient for the correlation between pAMPK and pACC scores in primary tumour samples was 0.514 (P=0.0002). Low pAMPK levels were associated with worse OS (P-value 0.0002) but not with PFS, whereas low pACC levels were associated both with worse OS and PFS (P-value 0.0007 and 0.01, respectively). Conclusions: Our findings suggest that high tissue AMPK activation is a prognostic biomarker in this cohort of metastatic colorectal cancer patients.
    British Journal of Cancer 06/2014; 111(1). DOI:10.1038/bjc.2014.274 · 4.82 Impact Factor
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